Biomaterials elicit an inflammatory response leading to the formation of destructive foreign giant cells (FBGC) that participate in the encapsulating foreign body response (FBR). We have discovered that the chemokine MCP-1 is required for FBGC formation and plays a role in the FBR. In addition, we recently demonstrated deregulation of matrix metalloproteinase (MMP)-9 in MCP-1-null macrophages and confirmed the importance of this enzyme in FBGC formation. Preliminary studies suggest the existence of a macrophage fusion mechanism involving induction of MMP-9 and E-cadherin expression. Taken together, our investigation of MCP-1-null macrophages revealed numerous mechanistic links during the fusion of macrophages and showed that the FBR displays extensive tissue specificity. In this application we propose studies to elucidate the mechanism of macrophage activation and FBGC formation and identify molecular determinants of the FBR. In addition, we aim to translate some of the acquired knowledge into a feasible bioengineering strategy to attenuate the FBR in the brain and in the context of a novel alginate scaffold. Accordingly, the specific aims of this application are: 1. to test the hypothesis that the function of MCP-1 during the FBR involves modulation of macrophage activation; 2. to test the hypothesis that MCP-1 participates in the brain FBR and modulates neuroinflammation and the integrity of the BBB; 3. to test the hypothesis that the requirement for MCP-1 in FBGC formation involves the activation of fusion-competent macrophages and involves induction of MMP-9 and cell surface-associated E-cadherin.; and 4. to engineer an alginate-based DNA delivery macroporous construct designed to modulate various aspects of the FBR in vivo. PUBLIC HEALTH RELEVANCE: Implantation of biomaterials, devices, and tissue engineered constructs into vascularized tissues elicits an inflammatory response the can lead to implant failure. A hallmark of this response is the fusion of inflammatory cells on the implant surface to form multinucleated giant cells that can be destructive. In addition, the inflammatory response leads to the eventual encapsulation of the implant resulting in lack of integration. In this application we propose to explore the molecular signals that regulate the formation of giant cells and develop biomaterials with the inherent ability to modulate the inflammatory response they elicit. Completion of this project should lead to a greater understanding of the events at the interface between living tissues and biomaterials.